Development and evaluation of magnetic microemulsion: tool for targeted delivery of camptothecin to BALB/c mice-bearing breast cancer

Abstract

Purpose: Development and evaluation of camptothecin-loaded-microemulsion (ME) and -magnetic microemulsion (MME) for passive/active-targeted delivery to BALB/c mice-bearing breast cancer.

Methods: Based on the pseudo-ternary phase diagrams camptothecin-loaded-MEs and -MMEs were developed using benzyl alcohol:Captex 300 (3:1), TPGS:Tween 80 (2:1) and water. Furthermore, characterized for their droplet size distribution, magnetic susceptibility and effect of droplet size in plasma and evaluated for in vitro and in vivo targeting potential, drug release, haemolytic potential, cytotoxicity, genotoxicity, in vivo biodistribution and lactone ring stability.

Results: Drug-loaded MEs showed uniform droplet distribution, extended drug release (76.07?±?4.30% at 24?h), acceptable level of haemolytic activity (<20%), significant cytotoxicity (129?±?3.9?ng/mL) against MCF-7 cancer cells and low DNA damage in lymphocytes. Targeting potential of MMEs was documented in 4T1 breast cancer-induced BALB/c mice. MMEs were concentrated more at the target tissue on introduction of external magnetic field. In vivo biodistribution study documented the active targeting of 5067.56?±?354.72?ng/gm and passive targeting of 1677.58?±?134.20?ng/gm camptothecin to breast cancer from MME and ME, respectively. Lactone stability study shows around 80% of the lactone stable at 24?h.

Conclusions: Developed ME and MME may act as a promising nanocarrier for efficient targeting of breast cancer tissues.     

Nanoemulsion gel-based topical delivery of an antifungal drug: in vitro activity and in vivo evaluation

Abstract

Objective: In this study, attempt has been focused to prepare a nanoemulsion (NE) gel for topical delivery of amphotericin B (AmB) for enhanced as well as sustained skin permeation, in vitro antifungal activity and in vivo toxicity assessment.

Materials and methods: A series of NE were prepared using sefsol-218 oil, Tween 80 and Transcutol-P by slow spontaneous titration method. Carbopol gel (0.5%?w/w) was prepared containing 0.1%?w/w AmB. Furthermore, NE gel (AmB-NE gel) was characterized for size, charge, pH, rheological behavior, drug release profile, skin permeability, hemolytic studies and ex vivo rat skin interaction with rat skin using differential scanning calorimeter. The drug permeability and skin irritation ability were examined with confocal laser scanning microscopy and Draize test, respectively. The in vitro antifungal activity was investigated against three fungal strains using the well agar diffusion method. Histopathological assessment was performed in rats to investigate their toxicological potential.

Results and discussion: The AmB-NE gel (18.09?±?0.6?µg/cm²/h) and NE (15.74?±?0.4?µg/cm²/h) demonstrated the highest skin percutaneous permeation flux rate as compared to drug solution (4.59?±?0.01?µg/cm²/h) suggesting better alternative to painful and nephrotoxic intravenous administration. Hemolytic and histopathological results revealed safe delivery of the drug. Based on combined results, NE and AmB-NE gel could be considered as an efficient, stable and safe carrier for enhanced and sustained topical delivery for AmB in local skin fungal infection.

Conclusion: Topical delivery of AmB is suitable delivery system in NE gel carrier for skin fungal infection.     

Novel non-ionic surfactant proniosomes for transdermal delivery of lacidipine: optimization using 23 factorial design and in vivo evaluation in rabbits

Abstract

Context: Proniosomes offer a versatile vesicle drug delivery concept with potential for delivery of drugs via transdermal route.

Objectives: To develop proniosomal gel using cremophor RH 40 as non-ionic surfactant containing the antihypertensive drug lacidipine for transdermal delivery so as to avoid its extensive first pass metabolism and to improve its permeation through the skin.

Materials and methods: Proniosomes containing 1% lacidipine were prepared by the coacervation phase separation method, characterized, and optimized using a 2³ full factorial design to define the optimum conditions to produce proniosomes with high entrapment efficiency, minimal vesicle size, and high-percentage release efficiency. The amount of cholesterol (X₁), the amount of soya lecithin (X₂), and the amount of cremophor RH 40 (X₃) were selected as three independent variables.

Results and discussion: The system F4 was found to fulfill the maximum requisite of an optimum system because it had minimum vesicle size, maximum EE, maximum release efficiency, and maximum desirability. The optimized system (F4) was then converted to proniosomal gel using carbopol 940 (1% w/w). In vitro permeation through excised rabbit skin study revealed higher flux (6.48?±?0.45) for lacidipine from the optimized proniosomal gel when compared with the corresponding emulgel (3.04?±?0.13) mg/cm²/h. The optimized formulation was evaluated for its bioavailability compared with commercial product. Statistical analysis revealed significant increase in AUC (0???α) 464.17?±?113.15?ng h/ml compared with 209.02?±?47.35?ng h/ml for commercial tablet. Skin irritancy and histopathological investigation of rat skin revealed its safety.

Conclusions: Cremophor RH 40 proniosomal gel could be considered as very promising nanocarriers for transdermal delivery of lacidipine.     

Cationic polymer-based micro-emulgel with self-preserving ability for transdermal delivery of diclofenac sodium

Abstract

The objective of the present study was to develop a topical preparation with enhanced skin permeation, high safety and self-preserving ability. Microemulsion (ME) and cationic polymer based micro-emulgel (CPBM) were investigated for the transdermal delivery of diclofenac sodium (DS). Medium-chain triglyceride was selected as the oil phase of ME due to its good solubilization of DS and high safety. Orthogonal test was applied to optimize the formula of ME based on the cumulative skin permeation amount in vitro after preliminary formula test. Chitosan (CS) or polylysine was employed as the cationic polymer in the formula of CPBM. The transdermal delivery of DS was evaluated through in vitro skin permeation test. The results showed that the skin permeation rate of DS from the optimized CPBM (126.17?±?15.82?μg/cm²/h) were 1.86-folds and 5.76-folds higher than that of DS commercial Emulgel and DS control hydrogel, respectively. MEs and the cationic polymer were found to have skin penetration co-enhancing effect when they were combined in the CPBM system. Furthermore, the CPBM showed a good growth inhibition of E. coli and S. aureus. The stability test revealed that the CPBM was stable at room temperature and 4?°C for a period of three months.     

Mometasone furoate-loaded cold processed oil-in-water emulsions: in vitro and in vivo studies

Abstract

Over the years, research has focused on strategies to increase benefit/risk ratio of corticoids. However, vehicles intended for topical glucocorticoids delivery with an improved benefit/risk ratio are still on demand. The aim of this work was the in vitro and in vivo characterization of cold processed oil-in-water (o/w) emulsions intended for mometasone furoate (MF) delivery to induce drug targeting to upper skin strata, decreasing adverse effects. Two o/w emulsions, containing 0.1% of MF, were developed differing in the glycol used (2-methyl-2,4-pentanediol – PT and ethoxydiglycol – TC emulsions). In vitro permeation studies revealed that these emulsions are suitable vehicles for the delivery of MF containing ingredients which are responsible for a drastically increased on the permeability coefficients of MF from a theoretical value of 1.18?×?10^?4?cm/h to 5.20?×?10^?4?±?2.05?×?10^?4?cm/h and 6.30?×?10^?4?±?2.94?×?10^?4?cm/h, for PT and TC, respectively. The tape stripping results showed that the amount of drug that reached the viable skin layers was very low (1.99 %) and the amount that remained in the stratum corneum (SC) was 10.61%. The in vivo studies showed that the developed formulations decreased the edema and erythema in mice skin in more that 90%, assuring, at least, the same anti-inflammatory effect compared with the commercial cream. PT placebo demonstrated to contribute to restore the skin barrier by increasing the amount of lipids within the human skin.     

Investigating effect of microemulsion components: In vitro permeation of ketoconazole

The purpose of this study was to evaluate the effect of oil, surfactant/co-surfactant mixing ratios and water on the in vitro permeation of ketoconazole (KTZ) applied in O/W microemulsion vehicle through intact rat skin. Lauryl Alcohol (LA) was screened as the oil phase of microemulsions, due to a good solubilizing capacity of the microemulsion system. The pseudo-ternary phase diagrams for microemulsion regions were constructed using LA as the oil, Labrasol (Lab) as the surfactant (S) and ethanol (EtOH) as the cosurfactant (CoS). The formulation which showed a highest permeation rate of 54.65?±?1.72 µg/cm²/h¹ and appropriate physico-chemical properties was optimized as containing 2% KTZ, 10% LA, 20% Lab/EtOH (1:1) and 68% double distilled water (w/w). The efficiency of microemulsion formulation in the topical delivery of KTZ was dependent upon the contents of water and LA as well as Lab/EtOH mixing ratio. It was concluded that the percutaneous absorption of KTZ from microemulsions was enhanced with increasing the LA and water contents, and with decreasing the Lab/EtOH ratio in the formulation. Candida albicans was used as a model fungus to evaluate the antifungal activity of the best formula achieved, which showed the widest zone of inhibition as compared to KTZ reference. The studied microemulsion formulation showed a good stability for a period of three months. Histopathological investigation of rat skin revealed the safety of microemulsion formulations for topical use. These results indicate that the studied microemulsion formulation might be a promising vehicle for topical delivery of KTZ.     

Assessment of the drug loading,in vitro and in vivo release behavior of novel pH-sensitive hydrogel

Context: As a glucocorticoid drug, dexamethasone has good therapeutic effects for ulcerative colitis. pH-sensitive hydrogels could make conventional changes of volume in response with different pH values. Meanwhile, they could load drugs depending on its internal three-dimensional network structure.

Objective: Appropriate methods were used to improve the drug-loading capacity of hydrogel and exploring the colon-targeting character of dexamethasone hydrogel.

Materials and methods: Different solvents (ethanol and 1,2-propanediol) were employed to dissolve dexamethasone as well as hydrogel monomer materials (poly(ethylene glycol) methyl ether (MPEG)–poly(lactide acid)–acryloyl chloride macromonomer, itaconic acid (IA) and MPEG–methacrylate), then mixing them together to prepare hydrogel through the heat-initiated free radical polymerization method. Differential scanning calorimetry and X-ray diffraction methods were used to verify whether dexamethasone was loaded into hydrogels. In vitro drug release behavior and in vivo pharmacokinetic study were also investigated in detail.

Results: Dexamethasone was successfully loaded into hydrogel, and its loading capacity was improved (5?mg/g). Both the in vitro release study and the in vivo pharmacokinetic study showed the good colon-targeting character of the pH-sensitive P(LE–IA–MEG) hydrogel (T_max?=?1.0?h, C_max?=?2.16?µg/ml of dexamethasone; T_max?=?3.9?h, C_max?=?0.43?µg/ml of dexamethasone hydrogel).

Discussion: Dexamethasone could be targeted to the colon site by P(LE–IA–MEG) hydrogel, thereby improving its therapeutic effect and reduce its side effects.

Conclusion: P(LE–IA–MEG) hydrogel might have great potential application in colon-targeted drug delivery systems.     

Formulation development,in vitro and in vivo evaluation of microemulsion-based gel loaded with ketoprofen

Abstract

Background: Anti-inflammatory agents are widely used to relieve inflammation caused by various factors.

Aim: This study was initiated with the intention to deliver low aqueous soluble ketoprofen to enhance its solubility by developing microemulsion system as a template and then incorporating it into gel phase.

Materials and methods: Initially ketoprofen was solubilized into microemulsion preparation made up of clove oil, Tween 20 and propylene glycol as oil phase, surfactant and co-surfactant respectively, then it was incorporated into different concentration of gelling phase using gelling agents namely Carbopol 940, Carbopol 934 and hydroxypropyl methyl cellulose K₄M (HPMC K₄M). Formulated emulgels were evaluated for their physical appearance, pH, rheological properties, globule size, extrudability, drug content, spreadability, bioadhesion strength, in vitro and ex vivo drug release, skin irritation test and anti-inflammatory activity.

Results: Microemulsion had shown globule size 396?nm, pH 6–6.7, viscosity 29.4?cps and zeta potential ?12?mV indicating good stability. Formulated emulgels showed good physical appearance, skin acceptable pH 6–6.9, non-Newtonian shear thinning system, drug content 99.28?±?0.16%, bioadhesion strength 48.4 gram force, globule size 473?nm, spreadability 22.96?gm.cm/s, good extrudability, in vitro release, ex vivo release did not showed any irritation reaction and possess a good anti-inflammatory activity.

Conclusions: Selected batch showed enhanced drug release (92.42?±?4.66%) as compared to marketed gel (65.94?±?3.30). Similarly ex vivo release of formulation showed 72.22% release through mice skin compared with marketed gel. Formulations followed Korsmeyer–Peppas diffusion kinetic model. It was observed from the results that the formulated emulgel can provide promising delivery of ketoprofen.     

Imiquimod-oleic acid prodrug-loaded cream reduced drug crystallinity and induced indistinguishable cytotoxicity and apoptosis in mice melanoma tumour

Abstract

In the present investigation, imiquimod (IMQ) was coupled to oleic acid (OLA; IMQ-OLA) to synthesise prodrug to reduce crystallinity that later amalgamated with oil-in-water (o/w) emulsion cream (IMQ-OLA cream) for the treatment of melanoma tumour. The synthesis of IMQ-OLA prodrug was verified by FT-IR, ¹HNMR and mass spectroscopy. The crystalline lattice of IMQ was transformed to somewhat amorphous structure in IMQ-OLA prodrug. IMQ-OLA cream retained 35.6% of IMQ within skin, significantly (p?<?0.05) higher than 22.3% and 10.6% retained by marketed IMQ cream and IMQ solution, respectively. IMQ-OLA cream suppressed the melanoma tumour to 70.3?mm³ in C57BL6J mice as compared to 72.6?mm³ tumour, reduced by marketed IMQ cream with no significant difference (p?>?0.05) at day 32 over 17-day period of treatment. IMQ-OLA cream followed the multiple mechanisms of cell death. IMQ-OLA cream warrants further in depth investigations for translating in to a clinically viable topical dermal product.     

Microemulsion-based delivery of triamcinolone acetonide to posterior segment of eye using chitosan and butter oil as permeation enhancer: an in vitro and in vivo investigation

The aim of the study was to formulate a microemulsion (ME) using chitosan (CH) and the butter oil (BO) as a permeation enhancer for targeting drug to the posterior segment of the eye, via topical route. Triamcinolone acetonide (TA) was selected as the model drug since it undergoes extensive first-pass metabolism, leading to poor oral bioavailability of 23%. For optimisation of BO concentration, different ratios of TA:BO were prepared by simple physical mixing in the ratio of 1:9 to 9:1 and diffusion study was performed. MEs containing TA, TA:BO and TA CH ME were formulated by water titration method. Globule sizes of TA ME, TA:BO ME and TA CH ME were found to be 66.06?±?0.32?nm, 78.52?±?1.50?nm and 97.30?±?2.50?nm, respectively. In ex vivo diffusion studies using goats eye, TA:BO ME (31.33?±?0.46 and 33.98?±?0.23) and TA CH ME (24.10?±?0.41 and 27.00?±?0.18) showed higher percentage of drug diffusion in comparison to TA ME (13.29?±?0.41and 15.56?±?0.34) and TA solution (8.20?±?1.04 and 10.39?±?0.22) in presence and in absence of vitreous humour. Fluorescence intensity of coumarin-6 (as a marker) loaded ME with BO and CH was found to be higher, confirming their role in altering membrane permeability and facilitating coumarin-6 diffusion to the posterior chamber. Overall, it was concluded that BO enhances the bioavailability of TA across the retina, thereby proving its potential as permeation enhancer in facilitating drug delivery to the posterior segment of the eye.     

Novel dithranol phospholipid microemulsion for topical application: development,characterization and percutaneous absorption studies

The objective of this study was to develop and characterize a novel dithranol-containing phospholipid microemulsion systems for enhanced skin permeation and retention. Based on the solubility of dithranol, the selected oils were isopropyl myristate (IPM) and tocopherol acetate (TA), and the surfactants were Tween 80 (T80) and Tween 20 (T20). The ratios of cosurfactants comprising of phospholipids and ethanol (1?:?10) and surfactant to co-surfactant (1?:?1 and 2.75?:?1) were fixed for the phase diagram construction. Selected microemulsions were evaluated for globule size, zeta potential, viscosity, refractive index, per cent transmittance, stability (freeze thaw and centrifugation), ex vivo skin permeation and retention. The microemulsion systems composed of IPM and T80 with mean particle diameter of 72.8?nm showed maximum skin permeation (82.23%), skin permeation flux (0.281?mg/cm²/h) along with skin retention (8.31%) vis-à-vis systems containing TA and T20. The results suggest that the developed novel lecithinized microemulsion systems have a promising potential for the improved topical delivery of dithranol.     

Chemical composition and biological activities of Helicteres vegae and Heliopsis sinaloensis

Context: Helicteres vegae Cristóbal (Sterculiaceae) (Hv) and Heliopsis sinaloensis B.L. Turner (Asteraceae) (Hs) are endangered and poorly studied plant species; related plants have been used against chronic-degenerative and infectious diseases. Therefore, Hv and Hs could be sources of bioactive compounds against these illnesses.

Objective: To determine the chemical composition and biological activities (antioxidant, antimutagenic and antimicrobial) of Hv and Hs leaves (L) and stems (S).

Materials and methods: Methanol extracts (ME) of each plant/tissue were evaluated for their phytochemicals; phenolics (HPLC-DAD-ESI-MS); antioxidant activity (AA) (0.125–4?mg/mL) (DPPH, ABTS, ORAC and β-carotene discoloration); antimutagenicity (0.5 and 1?mg/plate) (Ames assay, tester strain Salmonella enterica serovar Typhimurium YG1024, 1-nitropyrene as mutagen); activity against human pathogens (1?mg/mL); and toxicity (0.01–2?mg/mL) (Artemia salina assay).

Results: All ME showed flavonoids and triterpenes/steroids. The ME-SHv had the highest content of total phenolics (TP) (2245.82?±?21.45?mg GAE/100?g d.w.) and condensed tannins (603.71?±?1.115?mg CE/100?g d.w.). The compounds identified were flavonoids (kaempferol 7-O-coumaroylhexoside, and two kaempferol 7-O-rhamnosylhexosides) and phenolics [rosmarinic acid, and 3′-O-(8″-Z-caffeoyl) rosmarinic acid]. The ME-LHs showed the highest content of flavonoids (357.88?mg RE/g d.w.) and phenolic acids (238.58?mg CAE/g d.w.) by HPLC. The ME-SHv showed the highest AA. All ME were strong antimutagens (63.3-85.7%). Only the Hs extracts were toxic (ME-LHs, LC₅₀?=?94.9?±?1.7?μg/mL; ME-SHs, LC₅₀?=?89.03?±?4.42?μg/mL).

Discussion and conclusions: Both Hv and Hs are potential sources of preventive and therapeutic agents against chronic-degenerative diseases.     

Preparation and evaluation of dl-praeruptorin A microemulsion based hydrogel for dermal delivery

Abstract

The purpose of the present investigation was to develop and optimize the microemulsion (ME) as a transdermal system for Pd-Ia, a poor water soluble and low bioavailable drug. The pseudo-ternary phase diagrams were constructed for various ME formulations including oleic acid as the oil phase, Cremophor RH40 as the surfactant, ethanol as the cosurfactant, and water. The maximum cumulative amount permeated through rat abdominal skins per unit area in 32?h (Q₃₂), and the maximum flux were evaluated using the Franz diffusion cell in order to optimize the ME formulation. The results indicated that the optimized ME formulation was composed of oleic acid (5%, W/W), Cremophor RH40 (13.33%, W/W), ethanol (26.67%, W/W), and water (55%, W/W); the maximum cumulative amount of Pd-Ia was 354.330?±?12.006?μg?cm^?2, the maximum flux was 11.467?±?0.500?μg?cm^?2?h^?1. ME-gel was administered transdermally to rats. The mean plasma concentration of Pd-Ia following transdermal application of ME-gel could be maintained for 32?h at least and the half-life was evidently prolonged. It shows that the ME-gel could be a promising vehicle for dermal delivery of Pd-Ia.     

Efficacy and safety of stabilised hydrogen peroxide cream (Crystacide) in mild-to-moderate acne vulgaris: a randomised,controlled trial versus benzoyl peroxide gel

Background: Benzoyl peroxide (BP) is a first-line topical treatment in acne vulgaris (AV). However, its use can cause mild skin irritation and dryness. A new formulation of hydrogen peroxide stabilised (HPS) in monoglycerides cream (Crystacide 1%), indicated in the topical treatment of superficial skin infections, is now available as an alternative treatment.

Study aim: To evaluate efficacy and local tolerability of HPS in mild-to-moderate AV in comparison with BP gel.

Methods and patients: In a randomised, prospective, investigator-masked parallel-group, 8-week trial, 60 patients (24 men, 36 women, mean age 25?±?6 years) with mild-to-moderate AV, affecting mainly the face, were enrolled in the study, after their informed consent. HPS or BP (PanOxyl gel 4%) was applied topically twice daily for 8 weeks.

Study outcomes: The study endpoints were: (1) Reduction in mean inflammatory (IL), non-inflammatory (NIL) and total (TL) acneic lesions in comparison with baseline; (2) Local tolerability assessed evaluating erythema, dryness and burning sensation, using a 0-3 qualitative score (score 0?=?poor tolerability; score 3?=?very good tolerability).

Results: TL, NIL, and IL were assessed by an investigator unaware of treatment allocation at baseline, and week 8. The tolerability score (TS) was assessed at week 4 and 8. At baseline, the two groups were well matched for the main clinical and demographic characteristics. All patients concluded the trial. At week 0, in the HPS group TL, NIL and IL (mean?±?SD) were: 35?±?8, 20?±?6 and 16?±?7. At week 8, HPS reduced TL to 16?±?7; NIL to 9?±?3 and IL to 7?±?3 (p?<?0.001). At baseline, TL, NIL and IL, in the BP group, were 32?±?9, 24?±?8 and 18?±?7, respectively. At week 8, BP reduced TL, NIL and IL to 14?±?9; 7?±?5 and 7?±?3 (p?<?0.001). In comparison with baseline values, the percentage reductions of IL were 58% and 61% for HPS and BP, respectively (p?=?n.s.). At the end of the study the TS was 2.9?±?0.2 in HPS group and 2.4?±?0.8 in BP group (p?<?0.025). Two patients in HPS group (6%) and seven patients (23%) in BP group suffered from mild-to-moderate local erythema.

Conclusions: HPS has shown to be as effective as BP in reducing both inflammatory and noninflammatory AV lesions in patients with mild-to-moderate disease. In comparison with BP 4% gel, HPS cream shows a better local tolerability profile.     

Nanovesicular carrier-based formulation for skin cancer targeting: evaluation of cytotoxicity,intracellular uptake,and preclinical anticancer activity

Context: Skin cancer has turned into global epidemic leading to higher incidences among cancer stricken population.

Objective: The aim of the present investigation is to evaluate the anticancer potential and intracellular uptake of a novel nanovesicular formulation of 5-FU.

Materials and methods: Detailed intracellular uptake study in conjunction with estimation of intracellular reactive oxygen species was done using skin melanoma cell lines (A375) along with cytotoxicity studies. To further obtain the mechanistic insights into inhibition of tumor cell proliferation, cell-cycle arrest studies were conducted. The preclinical anticancer activity was carried out employing in vivo DMBA–croton oil-induced skin cancer model in mice.

Results and discussion: Significant reduction in the number of papillomas was observed in skin cancer-bearing mice on treatment with nanovesicular formulation (51.4?±?3.2%) in comparison with marketed formulation (21.3?±?2.1%) of 5-FU. Tumor volume was found to be reduced to 46.3?±?3.5% with prepared formulation, whereas the marketed formulation-treated group showed the reduction of 18.6?±?1.8% in comparison with the control (untreated) group.

Conclusion: The results of present study demonstrated that nanovesicular formulation of 5-FU possessed the enhanced anticancer activity which could be attributed to better intracellular uptake, cellular retention, and sustained release of drug.     

Paliperidone microemulsion for nose-to-brain targeted drug delivery system: pharmacodynamic and pharmacokinetic evaluation

Objective: The objective of present study was to develop and evaluate paliperidone (PALI) loaded microemulsion (PALI-ME) for intranasal delivery in the treatment of schizophrenia.

Material and methods: The PALI-ME was formulated by the spontaneous microemulsification method and characterized for physicochemical parameters. Pharmacodynamic assessments (apomorphine-induced compulsive behavior and spontaneous motor activity) were performed using mice. All formulations were tagged with ^99mTc (technetium). Pharmacokinetic evaluation of PALI in the brain was investigated using Swiss albino rats. Brain scintigraphy imaging was performed in rabbits.

Results and discussion: PALI-ME was found stable with average droplet size of 20.01?±?1.28?nm. In pharmacodynamic studies, significant (p?<?0.05) deference in parameters estimated, were found between the treated and control groups. ^99mTc-tagged PALI solution (PALI-SOL)/PALI-ME/PALI muco-adhesive ME (PALI-MME) was found to be stable and suitable for in vivo studies. Brain-to-blood ratio at all sampling points up to 8?h following intranasal administration of PALI-MME compared to intravenous PALI-ME was found to be 6–8 times higher signifying greater extent of distribution of the PALI in brain. Rabbit brain scintigraphy demonstrated higher intranasal uptake of the PALI into the brain.

Conclusion: This investigation demonstrates a prompt and larger extent of transport of PALI into the brain through intranasal PALI-MME, which may prove beneficial for treatment of schizophrenia.     

Skin irritation and the inhibition effect on HSV-1 in vivo of penciclovir-loaded microemulsion

The purpose of the present study was to investigate the skin irritation and pharmacodynamics of penciclovir-loaded microemulsion (PCV-ME). The formulation of PCV-ME was comprised of oleic acid (OA) (5%, w/w), Cremorphor EL (20%, w/w), ethanol (30%, w/w) and water (45%, w/w). PCV-ME presented as spherically shaped under transmission electron microscopy with an average diameter of 36.5 nm, and the solubility of PCV in microemulsion (ME) was 7.41 mg/g, almost 6 times that in water. Skin irritation test was performed in male guinea pigs, which demonstrated that no irritation effect was caused after single or multiple applications of PCV-ME. Likewise, male guinea pigs were employed as animal models which were infected with herpes simplex virus type 1 (HSV-1) in pharmacodynamics study. Real-time PCR was utilized to investigate the inhibition effect on HSV-1 exerted by commercial PCV-cream and PCV-ME. The results indicated that compared with commercial PCV-cream, PCV-ME could significantly inhibit the replication of HSV-1 in skin. In conclusion, PCV-ME could be a promising formulation which possessed the virtues of low irritation and high effectiveness.     

Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to irreversible loss of neurons, cognition and formation of abnormal protein aggregates. Rivastigmine, a reversible cholinesterase inhibitor used for the treatment of AD, undergoes extensive first-pass metabolism, thus limiting its absolute bioavailability to only 36% after 3-mg dose. Due to extreme aqueous solubility, rivastigmine shows poor penetration and lesser concentration in the brain thus requiring frequent oral dosing. This investigation was aimed to formulate microemulsion (ME) and mucoadhesive microemulsions (MMEs) of rivastigmine for nose to brain delivery and to compare percentage drug diffused for both systems using in-vitro and ex-vivo study. Rivastigmine-loaded ME and MMEs were prepared by titration method and characterized for drug content, globule size distribution, zeta potential, pH, viscosity and nasal ciliotoxicity study. Rivastigmine-loaded ME system containing 8% w/w Capmul MCM EP, 44% w/w Labrasol:Transcutol-P (1:1) and 48% w/w distilled water was formulated, whereas 0.3% w/w chitosan (CH) and cetyl trimethyl ammonium bromide (as mucoadhesive agents) were used to formulate MMEs, respectively. ME and MMEs formulations were transparent with drug content, globule size and zeta potential in the range of 98.59% to 99.43%, 53.8?nm to 55.4?nm and ?2.73?mV to 6.52?mV, respectively. MME containing 0.3% w/w CH followed Higuchi model (r²?=?0.9773) and showed highest diffusion coefficient. It was free from nasal ciliotoxicity and stable for three months. However, the potential of developed CH-based MME for nose to brain delivery of rivastigmine can only be established after in-vivo and biodistribution study.     

An in vivo study of Hypericum perforatum in a niosomal topical drug delivery system

The active compounds present in Hypericum perforatum L. (Hypericaceae) include hyperforin, hypericins and flavonoids, which are assumed to be responsible for the activity of the extract in the treatment of wounds and scars. The present study aimed to incorporate H. perforatum extract standardized to a known content of phloroglucinols, naphthodianthrones and polyphenolic compounds into an effective transdermal drug delivery system capable of entrapping both lipophilic and hydrophilic constituents in the form of niosomal gels for wound treatment. An 80% ethanol extract (HE) was prepared on a pilot scale using DIG-MAZ. An HPLC-DAD holistic profile was established for HE and was standardized to contain 3.4?±?4 rutin, 1.1?±?3 chlorogenic acid, 0.5?±?2 quercitrin, 2.8?±?2 hyperforin, and 0.51?±?3% w/w total hypericins. Niosomes were prepared using the modified reverse phase evaporation technique (REV). The wound healing effect of the gel was tested on 16 adult mongrel dogs. A significant decrease in the inflammatory cell count (18.4?±?5.3) was recorded in the niosomal gel 1.5% NaCMC-treated group at the 7th day post wounding. It induced a marked regression in the inflammatory phase and enhanced the early beginning of the proliferative phase of wound healing. After 21?days, it showed complete re-epithelization, formation of new matrix fibers and significant reduction in the wound size, compared to the control and the Panthenol® 2% cream treated groups. This is the first study of H. perforatum in a niosomal topical drug delivery system.     

Transdermal microemulsions of Boswellia carterii Bird: formulation,characterization and in vivo evaluation of anti-inflammatory activity

Abstract

Context: Boswellia species are trees (family: Bruseraceae) found in India, Northern Africa and the Middle East.

Objective: This study aims at formulating low dose biologically active fraction from the oleogum resin of Boswellia carterii (BC) in transdermal (TD) microemulsions (MEs) to acquire promoted anti-inflammatory efficacy.

Materials and methods: The bioactive fraction of the oleogum resin of BC was tested for solubility in different components. The most efficient were selected for constructing phase diagrams for ME preparation. The bioactive fraction was assayed by high performance liquid chromatography for 3-acetyl–11-keto-β-boswellic acid (AKBA), at 210?nm. The bioactive fraction was incorporated in 6?MEs. ME systems were evaluated for drug content and optimized systems were tested for characterization, permeation, skin irritancy and in vivo evaluation of anti-inflammatory activity.

Results and Discussion: Two systems were selected; ME1 and ME4 composed of Tween 80: PEG 400 at 1:1 and 2:1 ratio, with oil content 7.78 and 17.5%, respectively. The systems showed high encapsulation efficiency >83%, small droplet size <100?nm, and suitable pH for topical application. Permeation parameters for ME1 were higher compared to ME4. Both MEs were non irritant. ME1 showed significantly higher anti-inflammatory activity versus the standard TD anti-inflammatory piroxicam.

Conclusions: Optimized TD BC MEs could be used as a safe, effective and long acting alternative to oral anti-inflammatories, providing higher and prolonged efficacy and better patient compliance.